Chemical compounds

ABSTRACT

This invention relates to non-steroidal compounds that are modulators of androgen, glucocorticoid, mineralocorticoid, and progesterone receptors, and also to the methods for the making and use of such compounds.

FIELD OF THE INVENTION

This invention relates to non-steroidal compounds that are modulators ofandrogen, glucocorticoid, mineralocorticoid, and progesterone receptors,and also to the methods for the making and use of such compounds.

BACKGROUND OF THE INVENTION

Nuclear receptors are a class of structurally related gene expressionmodulators that act as ligand-dependent transcription factors (R. M.Evans, Science 240, 889 (1988)). The steroid receptors, namely theandrogen receptor, the estrogen receptor, the glucocorticoid receptor,the mineralocorticoid receptor, and the progesterone receptor representa subclass of the nuclear receptor superfamily. Nuclear receptor ligandsin this subclass exert their effects by binding to an intracellularsteroid hormone receptor. After the receptor-ligand complex istranslocated to the nucleus of the cell, the complex binds torecognition sites on DNA, which allows for the modulation of certaingenes.

Certain substances have demonstrated the ability to exhibit theiractivity in a tissue selective manner. In other words, tissueselectivity allows a nuclear receptor ligand to function as an agonistin some tissues, while having no effect or even an antagonist effect inother tissues. The term “selective receptor modulator” (SRM) has beengiven to these molecules. A synthetic compound that binds to anintracellular receptor and mimics the effects of the native hormone isreferred to as an agonist. A compound that inhibits the effect of thenative hormone is called an antagonist. The term “modulators” refers tocompounds that have a spectrum of activities ranging from full agonismto partial agonism to full antagonism. The molecular basis for thistissue selective activity is not completely understood. Without beinglimited to any particular explanation, particular ligands put nuclearreceptors in different conformational states. These states dictate theability of coactivators, corepressors, and other proteins to berecruited by the nuclear receptor (“NR”). The unique cofactor-NRensembles are the gene transcription factors that are thought tomodulate tissue selective effects.

Ligand-mediated effects through the action of nuclear receptors are notlimited to the classical genotropic mechanism outlined above. It isthought that some, if not all, of the separation of anabolic and generalhomeostatic effects from the stimulation of sexual tissues can beexplained by a particular ligand's ability to potentiate non-genotropicpathways. One example of liganded nuclear receptor induction ofnon-genotropic pathways is found in the work of S. C. Manolagas et al.,Cell, 104, 719-730. The action of a sex steroid NR on osteoblasts andother cell types is shown to involve the Src/Shc/ERK signaling pathway.This activity is mediated through the ligand binding domain of the sexsteroid nuclear receptor alone. The NR DNA-binding domain is notrequired to attenuate etoposide-induced apoptosis in HeLa cells. An NRlacking the DNA binding domain cannot function in the classical mode,acting as a transcription factor.

Nuclear receptor steroid ligands are known to play important roles inthe health of both men and women. In regard to men's health,testosterone (T) and dihydrotestosterone (DHT), for example, areendogenous steroidal ligands for the androgen receptor that likely playa role in every tissue type found in the mammalian body. During thedevelopment of the fetus, androgens play a role in sexualdifferentiation and development of male sexual organs. Further sexualdevelopment is mediated by androgens during puberty. Androgens playdiverse roles in the adult including stimulation and maintenance of malesexual accessory organs and maintenance of the musculoskeletal system.Cognitive function, sexuality, aggression, and mood are some of thebehavioral aspects mediated by androgens. Androgens affect the skin,bone, and skeletal muscle, as well as blood lipids and blood cells.

The study of androgen action and male reproductive dysfunction continuesto expand significantly. In fact, only recently has the definition of adisease state been associated with hormonal changes that occur in agingmen. This syndrome, previously referred to as Andropause, has morerecently been described as Androgen Deficiency in the Aging Male, or“ADAM” (A. Morales and J. L. Tenover, Urologic Clinics of North America(November 2002) 29(4) 975.) The onset of ADAM is unpredictable and itsmanifestations are subtle and variable. Clinical manifestations of ADAMinclude fatigue, depression, decreased libido, erectile dysfunction aswell as changes in cognition and mood.

Published information indicates that androgen replacement therapy (ART)in men may have benefits in terms of improving body compositionparameters (e.g. bone mineral density, increasing muscle mass, andstrength) as well as improving libido and mood in some men. Therefore,andrologists and other specialists are increasingly using ART for thetreatment of the symptoms of ADAM—though there is due caution givenandrogen's, like testosterone, potential side effects. Nonetheless,there is increasing scientific rational of and evidence for androgendeficiency and treatment in the aging male. Current testosterone-basedART therapies include injections, skin patches, gel-based formulations,and oral preparations. All of these therapies are somewhat efficaciousin the treatment of ADAM, but, due to the dramatic fluctuations inplasma T-levels following treatment, success with these therapies hasbeen variable.

Testosterone replacement products, such as AndroGel® (1% testosteronegel CIII, marketed by Solvay Pharmaceuticals) are emerging as atreatment of choice among physicians. Such products, however, fail tocorrectly mimic physiological testosterone levels and have potentialside effects including exacerbation of pre-existing sleep apnoea,polycythemia, and/or gynaecomastia. Furthermore, the longer-term sideeffects on target organs such as the prostate or the cardiovascularsystem are yet to be fully elucidated. Importantly, the potentialcarcinogenic effects of testosterone on the prostate prevent manyphysicians from prescribing it to older men (i.e. age >60 years) who,ironically, stand to benefit most from treatment. Also, all of theexisting treatment options have fundamental problems with their deliverymechanism. The need for a novel selective androgen receptor modulator(SARM) is obviated by the potential side effect profile manifested inconventional treatments. A SARM would ideally have all the beneficialeffects of endogenous androgens, while sparing sexual accessory organs,specifically the prostate.

In regard to female health, progesterone, the endogenous ligand for theprogesterone receptor (“PR”), plays an important role in femalereproduction during the various stages of the ovarian cycle and duringpregnancy. Among other things, progesterone prepares the endometrium forimplantation, regulates the implantation process, and helps maintainpregnancy. The therapeutic use of synthetic versions of progesterone(progestins) stems from progesterone's ability to regulate endometrialproliferation. In fact, progestins are included as part of hormonereplacement therapy (“HRT”) in women to reduce the incidence ofendometriosis. Unfortunately, the effectiveness of therapy is temperedby undesired side-effect profiles. Chronic progestin therapy orcontinuous estrogen replacement regimens are often associated withincreased bleeding. Excessive stimulatory effects on the endometrialvasculature may result in proliferation and fragility.

Compounds that modulate the effects of progesterone binding to PR arebelieved useful in the treatment and/or prophylaxis of endometriosis anduterine fibroid processes. Progesterone receptor antagonists such asmifepristone, also known as RU-486, and other PR modulators can inhibitendometrial proliferation at high estradiol concentrations in primates.Human clinical data with mifepristone supports the efficacy of a PRantagonist in endometriosis (D. R. Grow et. al., J. Clin. Endoctin.Metab. 1996, 81). Despite enthusiasm for its use, RU-486 also acts as apotent ligand for the glucocorticoid receptor (“GR”). Thiscross-reactivity with the GR is associated with homeostatic imbalances.

Thus, modulators of nuclear steroid hormones that are highly specificfor one receptor could offer greater benefit with less side effects inthe treatment of both female and male related hormone responsivediseases.

SUMMARY OF INVENTION

The present invention includes compounds of formula (I):

including salts, solvates, and physiologically functional derivativesthereof, wherein

-   -   R¹ is cyano, nitro, halogen, haloalkyl, heterocyclyl, hydroxy,        alkoxy, haloalkoxy, —OC(O)R⁶, —CO₂R⁶, —CONHR⁶, —C(O)R⁶,        —S(O),R⁶, —SO₂N(R⁶)₂, —NHC(O)R⁶, or —NHSO₂R⁶;    -   R² is H, cyano, nitro, halogen, haloalkyl, alkyl, alkenyl,        alkynyl, hydroxy, alkoxy, haloalkoxy, —OC(O)R⁶, or aryl;    -   R³ and R⁴each are independently —(CH₂)_(x)—R⁵,    -   where x is 0 to 6, and    -   R⁵ is selected from H, alkyl, hydroxy, haloalkyl, alkenyl,        alkynyl, cycloalkyl, heterocyclyl, —C(O)OR⁷, or —N(R⁸)₂;    -   each R⁶ independently is H, alkyl, alkenyl, alkynyl, cycloalkyl,        heterocyclyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;    -   each R⁷ independently is H, alkyl, cycloalkyl, aryl;    -   each R⁸ independently is H or alkyl; and    -   R⁹ is H, cyano, nitro, halogen, haloalkyl, alkyl, alkenyl,        alkynyl, hydroxy, alkoxy, haloalkoxy, —OC(O)R⁸, or aryl.

Preferably, R¹ is cyano, nitro, or halogen. In one embodiment, R³ is—(CH₂)_(x)—R⁵, x is 0, and R⁵ is H, alkyl, or haloalkyl. Haloalkyl,preferably, is trifluoromethyl or trifluoroethyl. In one embodiment R³is —(CH₂)_(x)—R⁵, x is 1, and R⁵ is cycloalkyl. In one embodiment R⁴ is—(CH₂)_(x)—R⁵, x is 0, and R⁵ is alkyl, cycloalkyl, or hydroxy. In oneembodiment R⁴ is —(CH₂)_(x)—R⁵, x is 1 to 6, and R⁵ is alkyl, alkenyl,haloalkyl, hydroxy, cycloalkyl, heterocyclyl, heteroaryl, or —N(R¹⁰)₂where each R¹⁰ is a C₁-C₆ alkyl group.

Preferred compounds of the present invention include:

-   -   N-(cyclopropylmethyl)-N-(4-nitro-1-naphthyl)-N-propylamine;    -   N-cyclohexyl-N-methyl-4-nitro-1-naphthalenamine;    -   N-(4-nitro-1-naphthyly-N,N-dipropylamine;    -   N-butyl-N-methyl-N-(4-nitro-1-naphthyl)amine;    -   4-[ethyl(2-methyl-2-propenyl)amino]-1-naphthonitrile;    -   N-butyl-N-ethyl-4-nitro-1-naphthalenamine;    -   4-[butyl(methyl)amino]-1-naphthonitrile;    -   4-[(cyclopropylmethyl)(propyl)amino]-1-naphthonitrile;    -   N¹-ethyl-N²,N²-dimethyl-N¹-(4-nitro-naphthyl)-1,2-ethanediamine;    -   4-(propylamino)-1-naphthonitrile;    -   4-[(3-hydroxypropyl)amino]-1-naphthonitrile;    -   3-[(4-nitro-1-naphthyl)amino]propan-1-ol;    -   4-[(cyclopropylmethyl)amino]-1-naphthalenecarbonitrile;    -   4{(cyclopropylmethyl)[3-(1-piperidinyl)propyl]amino}1-naphthalenecarbonitrile        trifluoroacetate;    -   4-[(cyclopropylmethyl)(3-hydroxypropyl)amino]-1-naphthalenecarbonitrile;    -   4-nitro-N-(2,2,2-trifluoroethyl)-1-naphthalenamine;    -   4-bromo-N-(2,2,2-trifluoroethyl)-1-naphthalenamine;    -   4-bromo-N,N-bis(2,2,2-trifluoroethyl)-1-naphthalenamine;    -   4-[(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile;    -   4-[bis(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile;    -   4-[propyl(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile;    -   4-[2-propen-1-yl(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile;        and    -   4-((2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile.

Another aspect of the present invention includes a compoundsubstantially as hereinbefore defined with reference to any one of theExamples.

Another aspect of the present invention includes a pharmaceuticalcomposition comprising a compound of the present invention and apharmaceutically acceptable carrier.

Another aspect of the present invention includes a compound of thepresent invention for use as an active therapeutic substance.

Another aspect of the present invention includes a compound of thepresent invention for use in the treatment or prophylaxis of conditionsor disorders that respond to selective androgen receptor modulation.

Another aspect of the present invention includes a compound of thepresent invention for use in the treatment or prophylaxis ofosteoporosis, muscle wasting, frailty, cardiovascular disease, breastcancer, uterine cancer, prostate hyperplasia, prostate cancer,dyslipidemia, menopausal vasomotor conditions, urinary incontinence,artherosclerosis, libido enhancement, depression, uterine fibroiddisease, aortic smooth muscle cell proliferation, endometriosis, orADAM.

Another aspect of the present invention includes the use of a compoundof the present invention in the manufacture of a medicament for use inthe treatment or, prophylaxis of conditions or disorders that respond toselective androgen receptor modulation.

Another aspect of the present invention includes using a compoundaccording to the present invention in the manufacture of a medicamentfor use in the treatment or prophylaxis of osteoporosis, muscle wasting,frailty, cardiovascular disease, breast cancer, uterine cancer,prostatic hyperplasia, prostate cancer, dyslipidemia, menopausalvasomotor conditions, urinary incontinence, artherosclerosis, libidoenhancement, depression, uterine fibroid disease, aortic smooth musclecell proliferation, endometriosis, or ADAM.

Another aspect of the present invention includes a method for thetreatment or prophylaxis of conditions or disorders that respond toselective androgen receptor modulation comprising the administration ofa compound according to the present invention.

Another aspect of the present invention includes a method for thetreatment or prophylaxis of osteoporosis, muscle wasting, frailty,cardiovascular disease, breast cancer, uterine cancer, prostatichyperplasia, prostate cancer, dyslipidemia, menopausal vasomotorconditions, urinary incontinence, artherosclerosis, libido enhancement,depression, uterine fibroid disease, aortic smooth muscle cellproliferation, endometiosis, or ADAM comprising the administration of acompound according to the present invention.

The compounds of the present invention modulate the function of thenuclear hormone receptors, particularly the androgen receptor (“AR”).The present invention includes compounds that are selective agonists,partial agonists, antagonists, or partial antagonists of the AR.Compounds of the present invention are useful in the treatment ofAR-associated diseases and conditions, for example, a disease orcondition that is prevented, alleviated, or cured through the modulationof the function or activity of AR. Such modulation may be isolatedwithin certain tissues or widespread throughout the body of the subjectbeing treated.

An aspect of the present invention is the use of the compounds of thepresent invention for the treatment or prophylaxis of a variety ofdisorders including, but not limited to, osteoporosis and/or theprevention of reduced bone mass, density, or growth, osteoarthritis,acceleration of bone fracture repair and healing, acceleration ofhealing in joint replacement, periodontal disease, acceleration of toothrepair or growth, Paget's disease, osteochondrodysplasias, musclewasting, the maintenance and enhancement of muscle strength andfunction, frailty or age-related functional decline (“ARFD”), dry eye,sarcopenia, chronic fatigue syndrome, chronic myaligia, acute fatiguesyndrome, acceleration of wound healing, maintenance of sensoryfunction, chronic liver disease, AIDS, weightlessness, burn and traumarecovery, thrombocytopenia, short bowel syndrome, irritable bowelsyndrome, inflammatory bowel disease, Crohn's disease and ulcerativecolitis, obesity, eating disorders including anorexia associated withcachexia or aging, hypercortisolism and Cushing's syndrome,cardiovascular disease or cardiac dysfunction, congestive heart failure,high blood pressure, malignant tumor cells containing the androgenreceptor including breast, brain, skin, ovary, bladder, lymphatic,liver, kidney, uterine, pancreas, endometrium, lung, colon, andprostate, prostatic hyperplasia, hirsutism, acne, seborrhea, androgenicalopecia, anemia, hyperpilosity, adenomas and neoplasis of the prostate,hyperinsulinemia, insulin resistance, diabetes, syndrome X,dyslipidemia, menopausal vasomotor conditions, urinary incontinence,artherosclerosis, libido enhancement, sexual dysfunction, depression,nervousness, irritability, stress, reduced mental energy and lowself-esteem, improvement of cognitive function, endometriosis,polycystic ovary syndrome, counteracting preeclampsia, premenstralsyndrome, contraception, uterine fibroid disease, aortic smooth musclecell proliferation, male hormone replacement, or ADAM.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Terms are used within their accepted meanings. The following definitionsare meant to clarify, but not limit, the terms defined.

As used herein the term “alkyl” refers to a straight or branched chainhydrocarbon, preferably having from one to twelve carbon atoms, whichmay be optionally substituted, with multiple degrees of substitutionincluded within the present invention. Examples of “alkyl” as usedherein include, but are not limited to, methyl, ethyl, propyl,isopropyl, isobutyl, n-butyl, tert-butyl, isopentyl, n-pentyl, andsubstituted versions thereof.

As used throughout this specification, the preferred number of atoms,such as carbon atoms, will be represented by, for example, the phrase“C_(x)-C_(y) alkyl,” which refers to an alkyl group, as herein defined,containing the specified number of carbon atoms. Similar terminologywill apply for other preferred terms and ranges as well.

As used herein the term “alkenyl” refers to a straight or branched chainis aliphatic hydrocarbon containing one or more carbon-to-carbon doublebonds that may be optionally substituted, with multiple degrees ofsubstitution included within the present invention. Examples include,but are not limited to, vinyl and the like and substituted versionsthereof.

As used herein the term “alkynyl” refers to a straight or branched chainaliphatic hydrocarbon containing one or more carbon-to-carbon triplebonds that may be optionally substituted, with multiple degrees ofsubstitution included within the present invention. Examples include,but are not limited to, ethynyl and the like and substituted versionsthereof.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical, preferably having from one to tencarbon atoms. Alkylene groups as defined herein may optionally besubstituted, with multiple degrees of substitution included within thepresent invention. Examples of “alkylene” as used herein include, butare not limited to, methylene (—CH₂—), ethylene (—CH₂—CH₂—), propylene(—CH₂—CH₂—CH₂—) as well as substituted and/or branched versions.

As used herein, the term “cycloalkyl” refers to an optionallysubstituted non-aromatic cyclic hydrocarbon ring, which optionallyincludes an alkylene linker through which the cycloalkyl may beattached, with multiple degrees of substitution included within thepresent invention. Exemplary “cycloalkyl” groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and substituted versions thereof.

As used herein, the terms “heterocycle,” “heterocyclic” or“heterocyclyl” refers to a mono- or poly-cyclic ring system containingoptionally one or more degrees of unsaturation, but not to overlap withheteroaryl, and also containing optionally one or more heteroatoms.Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfuroxides, and dioxides. Preferably the ring is three to ten-membered andis either saturated or has one or more degrees of unsaturation.Optionally, as used herein, the heterocycle may be substituted, withmultiple degrees of substitution being allowed. Such rings may beoptionally fused to one or more of another “heterocyclic” ring(s),heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s). Examples of“heterocyclic” groups include, but are not limited to, tetrahydrofuran,pyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine,tetrahydrothiopyran, and tetrahydrothiophene.

As used herein, the term “aryl” refers to an optionally substitutedbenzene ring or to an optionally substituted fused benzene ring system,for example anthracene, phenanthrene, or naphthalene ring systems.Multiple degrees of substitution are included within the presentdefinition. Examples of “aryl” groups include, but are not limited to,phenyl, 2-naphthyl, 1-naphthyl, biphenyl, and substituted derivativesthereof. The term “aralkyl” refers to an aryl group as defined hereinattached through an alkylene linker, such as, for example, benzyl.

As used herein, the term “heteroaryl” refers to an optionallysubstituted monocyclic five to seven membered aromatic ring, or to anoptionally substituted fused bicyclic aromatic ring system comprisingtwo of such aromatic rings, which contain one or more nitrogen, sulfur,and/or oxygen atoms, where N-oxides, sulfur oxides, and dioxides arepermissible heteroatom substitutions. Multiple degrees of substitutionare included within the present definition. Examples of “heteroaryl”groups used herein include, but should not be limited to, furan,thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole,oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine,pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran,benzothiophene, indole, indazole, and substituted versions thereof. Theterm “heteroaralkyl” refers to a heteroaryl group as defined hereinattached through an alkylene linker.

As used herein the term “halogen” refers to fluorine, chlorine, bromine,or iodine.

As used herein the term “haloalkyl” refers to an alkyl group, as definedherein that is substituted with at least one halogen. Examples ofbranched or straight chained “haloalkyl” groups useful in the presentinvention include, but are not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, and t-butyl substituted independently with one ormore halogens, e.g., fluoro, chloro, bromo, and iodo. The term“haloalkyl” should be interpreted to include such substituents such as—CF₃, —CH₂—CH₂—F, and the like.

As used herein the term “hydroxy” refers to a group —OH.

As used herein the term “alkoxy” refers to a group —OR_(a), where R_(a)is alkyl as defined.

As used herein the term “haloalkoxy” refers to a group —OR_(a), whereR_(a) is haloalkyl as defined.

As used herein the term “aryloxy” refers to a group —R_(b), where R_(b)is aryl as defined.

As used herein the term “heteroaryloxy” refers to a group —OR_(b), whereR_(b) is heteroaryl as defined.

As used herein the term “nitro” refers to the group —NO₂.

As used herein the term “cyano” refers to the group —CN.

As used herein throughout the present specification, the phrase“optionally substituted” or variations thereof denote an optionalsubstitution, including multiple degrees of substitution, with one ormore substituent group. The phrase should not be interpreted so as to beimprecise or duplicative of substitution patterns herein described ordepicted. Rather, those of ordinary skill in the art will appreciatethat the phrase is included to provide for obvious modifications, whichare encompassed within the scope of the appended claims.

Exemplary optional substituents include acyl; alkyl; alkenyl; alkynyl;alkylsulfonyl; alkoxy; cyano; halogen; haloalkyl; hydroxy; nitro; aryl,which may be further substituted with acyl, alkoxy, alkyl, alkenyl,alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro;heteroaryl, which may be further substituted with acyl, alkoxy, alkyl,alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, ornitro; arylsulfonyl, which may be further substituted with acyl, alkoxy,alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl,hydroxy, or nitro; heteroarylsulfonyl, which may be further substitutedwith acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano,halogen, haloalkyl, hydroxy, or nitro; aryloxy, which may be furthersubstituted with acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl,cyano, halogen, haloalkyl, hydroxy, or nitro; heteroaryloxy, which maybe further substituted with acyl, alkoxy, alkyl, alkenyl, alkynyl,alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro; or —N(R*)₂;where for each occurrence R* is independently selected from H, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl,heteroaralkyl, alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl, whereeach occurrence of such aryl or heteroaryl may be substituted with oneor more acyl, alkoxy, alkyl, alkenyl, alkylsulfonyl, cyano, halogen,haloalkyl, hydroxy, or nitro, or the two R's may combine to form a ring,optionally having additional heteroatoms, optionally having one or moredegrees of unsaturation, and optionally being further substituted withacyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen,haloalkyl, hydroxy, or nitro.

The compounds of formulas (I) may crystallize in more than one form, acharacteristic known as polymorphism, and such polymorphic forms(“polymorphs”) are within the scope of formula (I). Polymorphismgenerally can occur as a response to changes in temperature, pressure,or both. Polymorphism can also result from variations in thecrystallization process. Polymorphs can be distinguished by variousphysical characteristics known in the art such as x-ray diffractionpatterns, solubility, and melting point.

Certain of the compounds described herein contain one or more chiralcenters, or may otherwise be capable of existing as multiplestereoisomers. The scope of the present invention includes mixtures ofstereoisomers as well as purified enantiomers orenantiomerically/diastereomerically enriched mixtures. Also includedwithin the scope of the invention are the individual isomers of thecompounds represented by formula (I), as well as any wholly or partiallyequilibrated mixtures thereof. The present invention also includes theindividual isomers of the compounds represented by the formulas above asmixtures with isomers thereof in which one or more chiral centers areinverted.

Typically, but not absolutely, the salts of the present invention arepharmaceutically acceptable salts. Salts encompassed within the term“pharmaceutically acceptable salts” refer to non-toxic salts of thecompounds of this invention. Salts of the compounds of the presentinvention may comprise acid addition salts. Representative salts-includeacetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, monopotassium maleate,mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, potassium, salicylate, sodium, stearate, subacetate,succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide,trimethylammonium, and valerate salts. Other salts, which are notpharmaceutically acceptable, may be useful in the preparation ofcompounds of this invention and these should be considered to form afurther aspect of the invention.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound ofFormula I, or a salt or physiologically functional derivative thereof)and a solvent. Such solvents, for the purpose of the invention, shouldnot interfere with the biological activity of the solute. Non-limitingexamples of suitable solvents include, but are not limited to water,methanol, ethanol, and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent. Non-limiting examples of suitablepharmaceutically acceptable solvents include water, ethanol, and aceticacid. Most preferably the solvent used is water.

As used herein, the term “physiologically functional derivative” refersto any pharmaceutically acceptable derivative of a compound of thepresent invention that, upon administration to a mammal, is capable ofproviding (directly or indirectly) a compound of the present inventionor an active metabolite thereof. Such derivatives, for example, estersand amides, will be clear to those skilled in the art, without undueexperimentation. Reference may be made to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal, or human that is being sought, forinstance, by a researcher or clinician. The biological or medicalresponse may be considered a prophylactic response or a treatmentresponse. The term “therapeutically effective amount” means any amountwhich, as compared to a corresponding subject who has not received suchamount, results in improved treatment, healing, prevention, oramelioration of a disease, disorder, or side effect, or a decrease inthe rate of advancement of a disease or disorder. The term also includeswithin its scope amounts effective to enhance normal physiologicalfunction. For use in therapy, therapeutically effective amounts of acompound of formula (I), as well as salts, solvates, and physiologicalfunctional derivatives thereof, may be administered as the raw chemical.Additionally, the active ingredient may be presented as a pharmaceuticalcomposition.

Accordingly, the invention further provides pharmaceutical compositionsthat include effective amounts of compounds of the formula (I) andsalts, solvates, and physiological functional derivatives thereof, andone or more pharmaceutically acceptable carriers, diluents, orexcipients. The compounds of formula (I) and salts, solvates, andphysiologically functional derivatives thereof, are as herein described.The carrier(s), diluent(s) or excipient(s) must be acceptable, in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient of the pharmaceutical composition.

In accordance with another aspect of the invention there is alsoprovided a process for the preparation of a pharmaceutical formulationincluding admixing a compound of the formula (I) or salts, solvates, andphysiological functional derivatives thereof, with one or morepharmaceutically acceptable carriers, diluents or excipients.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors. For example, thespecies, age, and weight of the recipient, the precise conditionrequiring treatment and its severity, the nature of the formulation, andthe route of administration are all factors to be considered. Thetherapeutically effective amount ultimately should be at the discretionof the attendant physician or veterinarian. Regardless, an effectiveamount of a compound of formula (I) for the treatment of humanssuffering from frailty, generally, should be in the range of 0.1 to 100mg/kg body weight of recipient (mammal) per day. More usually theeffective amount should be in the range of 1 to 10 mg/kg body weight perday. Thus, for a 70 kg adult mammal the actual amount per day wouldusually be from 70 to 700 mg. This amount may be given in a single doseper day or in a number (such as two, three, four, five, or more) ofsub-doses per day such that the total daily dose is the same. Aneffective amount of a salt, solvate, or physiologically functionalderivative thereof, may be determined as a proportion of the effectiveamount of the compound of formula (I) per se. Similar dosages should beappropriate for treatment or prophylaxis of the other conditionsreferred to herein.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, as a non-limiting example, 0.5 mg to 1 g of acompound of the formula (I), depending on the condition being treated,the route of administration, and the age, weight, and condition of thepatient. Preferred unit dosage formulations are those containing a dailydose or sub-dose, as herein above recited, or an appropriate fractionthereof, of an active ingredient. Such pharmaceutical formulations maybe prepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by an oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal, or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions, each with aqueous or non-aqueousliquids; edible foams or whips; or oil-in-water liquid emulsions orwater-in-oil liquid emulsions. For instance, for oral administration inthe form of a tablet or capsule, the active drug component can becombined with an oral, non-toxic pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Generally,powders are prepared by comminuting the compound to a suitable fine sizeand mixing with an appropriate pharmaceutical carrier such as an ediblecarbohydrate, as, for example, starch or mannitol. Flavorings,preservatives, dispersing agents, and coloring agents can also bepresent.

Capsules are made by preparing a powder, liquid, or suspension mixtureand encapsulating with gelatin or some other appropriate shell material.Glidants and lubricants such as colloidal silica, talc, magnesiumstearate, calcium stearate, or solid polyethylene glycol can be added tothe mixture before the encapsulation. A disintegrating or solubilizingagent such as agar-agar, calcium carbonate or sodium carbonate can alsobe added to improve the availability of the medicament when the capsuleis ingested. Moreover, when desired or necessary, suitable binders,lubricants, disintegrating agents, and coloring agents can also beincorporated into the mixture. Examples of suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth, orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, andthe like. Lubricants useful in these dosage forms include, for example,sodium oleate, sodium stearate, magnesium stearate, sodium benzoate,sodium acetate, sodium chloride, and the like. Disintegrators include,without limitation, starch, methyl cellulose, agar, bentonite, xanthangum, and the like.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant, andpressing into tablets. A powder mixture may be prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove. Optional ingredients include binders such ascarboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone,solution retardants such as paraffin, resorption accelerators such as aquaternary salt, and/or absorption agents such as bentonite, kaolin, ordicalcium phosphate. The powder mixture can be wet-granulated with abinder such as syrup, starch paste, acadia mucilage or solutions ofcellulosic or polymeric materials, and forcing through a screen. As analternative to granulating, the powder mixture can be run through thetablet machine and the result is imperfectly formed slugs broken intogranules. The granules can be lubricated to prevent sticking to thetablet forming dies by means of the addition of stearic acid, a stearatesalt, talc or mineral oil. The lubricated mixture is then compressedinto tablets. The compounds of the present invention can also becombined with a free flowing inert carrier and compressed into tabletsdirectly without going through the granulating or slugging steps. Aclear or opaque protective coating consisting of a sealing coat ofshellac, a coating of sugar or polymeric material, and a polish coatingof w,ax can be provided. Dyestuffs can be added to these coatings todistinguish different unit dosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared, for example, bydissolving the compound in a suitably flavored aqueous solution, whileelixirs are prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated generally by dispersing the compound in anon-toxic vehicle. Solubilizers and emulsifiers such as ethoxylatedisostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives;flavor additives such as peppermint oil, or natural sweeteners,saccharin, or other artificial sweeteners; and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of formula (I) and salts, solvates, and physiologicalfunctional derivatives thereof, can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

The compounds of formula (I) and salts, solvates, and physiologicallyfunctional derivatives thereof may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled.

The compounds may also be coupled with soluble polymers as targetabledrug carriers. Such polymers can include polyvinylpyrrolidone (PVP),pyran copolymer, polyhydroxypropylmethacrylamide-phenol,polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug; for example, polylactic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986), incorporated herein by reference as related to such deliverysystems.

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations may be applied as a topical ointment orcream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles, and mouthwashes.

Pharmaceutical formulations adapted for nasal administration, where thecarrier is a solid, include a coarse powder having a particle size forexample in the range 20 to 500 microns. The powder is administered inthe manner in which snuff is taken, i.e., by rapid inhalation throughthe nasal passage from a container of the powder held close up to thenose. Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered dose pressurized aerosols, nebulizers, orinsufflators.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and solutes that renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question. For example, formulationssuitable for oral administration may include flavoring or coloringagents.

The compounds of the present invention and their salts, solvates, andphysiologically functional derivatives thereof, may be employed alone orin combination with other therapeutic agents for the treatment of theabove-mentioned conditions. For example, in frailty therapy, combinationmay be had with other anabolic or osteoporosis therapeutic agents. Asone example, osteoporosis combination therapies according to the presentinvention would thus comprise the administration of at least onecompound of formula (I) or a salt, solvate, or physiologicallyfunctional derivative thereof, and the use of at least one otherosteoporosis therapy. As a further example, combination therapiesaccording to the present invention include the administration of atleast one compound of formula (I) or a salt, solvate, or physiologicallyfunctional derivative thereof, and at least one other osteoporosistreatment agent, for example, an anti-bone resorption agent. Thecompound(s) of formula (I) and the other pharmaceutically activeagent(s) may be administered together or separately and, whenadministered separately, administration may occur simultaneously orsequentially, in any order. The amounts of the compound(s) of formula(I) and the other pharmaceutically active agent(s) and the relativetimings of administration will be selected in order to achieve thedesired combined therapeutic effect. The administration in combinationof a compound of formula (I) salts, solvates, or physiologicallyfunctional derivatives thereof with other treatment agents may be incombination by administration concomitantly in: (1) a unitarypharmaceutical composition including both compounds; or (2) separatepharmaceutical compositions each including one of the compounds.Alternatively, the combination may be administered separately in asequential manner wherein one treatment agent is administered first andthe other second or vice versa. Such sequential administration may beclose in time or remote in time.

Another potential osteoporosis treatment agent is a bone building(anabolic) agent. Bone building agents can lead to increases inparameters such as bone mineral density that are greater than those thancan be achieved with anti-resorptive agents. In some cases, suchanabolic agents can increase trabecular connectivity leading to greaterstructural integrity of the bone.

Other potential therapeutic combinations include the compounds of thepresent invention combined with other compounds of the presentinvention, growth promoting agents, growth hormone secretagogues, growthhormone releasing factor and its analogs, growth hormone and itsanalogs, somatomedins, alpha-ardenergic agonists, serotonin 5-HTDagonists, agents that inhibit somatostatin or its release, 5-α-reductaseinhibitors, aromatase inhibitors, GnRH agonists or antagonists,parathyroid hormone, bisphosphonates, estrogen, testosterone, SERMs,progesterone receptor agonists or antagonists, and/or with othermodulators of nuclear hormone receptors.

One skilled in the art will acknowledge that although the compoundsembodied herein will be used as selective agonists, partial agonists,and antagonists, compounds with mixed steroid activities may also beemployed.

The compounds of the present invention may be used in the treatment of avariety of disorders and conditions and, as such, the compounds of thepresent invention may be used in combination with a variety of othersuitable therapeutic agents useful in the treatment or prophylaxis ofthose disorders or conditions. Non-limiting examples includecombinations of the present invention with anti-diabetic agents,anti-osteoporosis agents, anti-obesity agents, anti-inflammatory agents,anti-anxiety agents, anti-depressants, anti-hypertensive agents,anti-platelet agents, anti-thrombotic and thrombolytic agents, cardiacglycosides, cholesterol or lipid lowering agents, mineralocorticoidreceptor antagonists, phosphodiesterase inhibitors, kinase inhibitors,thyroid mimetics, anabolic agents, viral therapies, cognitive disordertherapies, sleeping disorder therapies, sexual dysfunction therapies,contraceptives, cytotoxic agents, radiation therapy, anti-proliferativeagents, and anti-tumor agents. Additionally, the compounds of thepresent invention may be combined with nutritional supplements such asamino acids, triglycerides, vitamins, minerals, creatine, piloic acid,carnitine, or coenzyme Q10.

An aspect of the present invention is the use of the compounds of thepresent invention for the treatment or prophylaxis of a variety ofdisorders including, but not limited to, osteoporosis and/or theprevention of reduced bone mass, density, or growth, osteoarthritis,acceleration of bone fracture repair and healing, acceleration ofhealing in joint replacement, periodontal disease, acceleration of toothrepair or growth, Paget's disease, osteochondrodysplasias, musclewasting, the maintenance and enhancement of muscle strength andfunction, frailty or age-related functional decline (“ARFD”), dry eye,sarcopenia, chronic fatigue syndrome, chronic myaligia, acute fatiguesyndrome, acceleration of wound healing, maintenance of sensoryfunction, chronic liver disease, AIDS, weightlessness, bum and traumarecovery, thrombocytopenia, short bowel syndrome, irritable bowelsyndrome, inflammatory bowel disease, Crohn's disease and ulcerabvecolitis, obesity, eating disorders including anorexia associated withcachexia or aging, hypercortisolism and Cushing's syndrome,cardiovascular disease or cardiac dysfunction, congestive heart failure,high blood pressure, malignant tumor cells containing the androgenreceptor including breast, brain, skin, ovary, bladder, lymphatic,liver, kidney, uterine, pancreas, endometrium, lung, colon, andprostate, prostatic hyperplasia, hirsutism, acne, seborrhea, androgenicalopecia, anemia, hyperpilosity, adenomas and neoplasis of the prostate,hyperinsulinemia, insulin resistance, diabetes, syndrome X,dyslipidemia, menopausal vasomotor conditions, urinary incontinence,artherosclerosis, libido enhancement, sexual dysfunction, depression,nervousness, irritability, stress, reduced mental energy and lowself-esteem, improvement of cognitive function, endometriosis,polycystic ovary syndrome, counteracting preeclampsia, premenstralsyndrome, contraception, uterine fibroid disease, aortic smooth musclecell proliferation, male hormone replacement, or ADAM.

In particular, the compounds of the present invention are believeduseful, either alone or in combination with other agents, in thetreatment of and use as male and female hormone replacement therapy,hypogonadism, osteoporosis, muscle wasting, wasting diseases, cancercachexia, frailty, prostatic hyperplasia, prostate cancer, breastcancer, menopausal and andropausal vasomotor conditions, urinaryincontinence, sexual dysfunction, erectile dysfunction, depression,uterine fibroid disease, and/or endometriosis, treatment of acne,hirsutism, stimulation of hematopoiesis, male contraception, impotence,and as anabolic agents.

Another aspect of the present invention thus also provides compounds offormula (I) and salts, solvates, or physiologically functionalderivatives thereof, for use in medical therapy. Particularly, thepresent invention provides for the treatment or prophylaxis of disordersmediated by androgenic activity. More particularly, the presentinvention provides through the treatment or prophylaxis of disordersresponsive to tissue-selective anabolic and or androgenic activity. Afurther aspect of the invention provides a method of treatment orprophylaxis of a mammal suffering from a disorder mediated by androgenicactivity, which includes administering to said subject an effectiveamount of a compound of formula (I) or a salt, solvate, orphysiologically functional derivative thereof.

A further aspect of the invention provides a method of treatment orprophylaxis of a mammal requiring the treatment or prophylaxis of avariety of disorders including, but not limited to, osteoporosis and/orthe prevention of reduced bone mass, density, or growth, osteoarthritis,acceleration of bone fracture repair and healing, acceleration ofhealing in joint replacement, periodontal disease, acceleration of toothrepair or growth, Paget's disease, osteochondrodysplasias, musclewasting, the maintenance and enhancement of muscle strength andfunction, frailty or age-related functional decline (“ARFD”), dry eye,sarcopenia, chronic fatigue syndrome, chronic myaligia, acute fatiguesyndrome, acceleration of wound healing, maintenance of sensoryfunction, chronic liver disease, AIDS, weightlessness, bum and traumarecovery, thrombocytopenia, short bowel syndrome, irritable bowelsyndrome, inflammatory bowel disease, Crohn's disease and ulcerativecolitis, obesity, eating disorders including anorexia associated withcachexia or aging, hypercortisolism and Cushing's syndrome,cardiovascular disease or cardiac dysfunction, congestive heart failure,high blood pressure, malignant tumor cells containing the androgenreceptor including breast, brain, skin, ovary, bladder, lymphatic,liver, kidney, uterine, pancreas, endometrium, lung, colon, andprostate, prostatic hyperplasia, hirsutism, acne, seborrhea, androgenicalopecia, anemia, hyperpilosity, adenomas and neoplasis of the prostate,hyperinsulinemia, insulin resistance, diabetes, syndrome X,dyslipidemia, menopausal vasomotor conditions, urinary incontinence,artherosclerosis, libido enhancement, sexual dysfunction, depression,nervousness, irritability, stress, reduced mental energy and lowself-esteem, improvement of cognitive function, endometriosis,polycystic ovary syndrome, counteracting preeclampsia, premenstralsyndrome, contraception, uterine fibroid disease, aortic smooth musclecell proliferation, male hormone replacement, or ADAM. Preferably thecompounds of the present invention are used as male and female hormonereplacement therapy or for the treatment or prevention of hypogonadism,osteoporosis, muscle wasting, wasting diseases, cancer cachexia,frailty, prostatic hyperplasia, prostate cancer, breast cancer,menopausal and andropausal vasomotor conditions, urinary incontinence,sexual dysfunction, erectile dysfunction, depression, uterine fibroiddisease, and/or endometriosis, treatment of acne, hirsutism, stimulationof hematopoiesis, male contraception, impotence, and as anabolic agents,which use includes administering to a subject an effective amount of acompound of formula (I) or a salt, solvate, or physiologicallyfunctional derivative thereof. The mammal requiring treatment with acompound of the present invention is typically a human being.

The compounds of this invention may be made by a variety of methods,including well-known standard synthetic methods. Illustrative generalsynthetic methods are set out below and then specific compounds of theinvention are prepared in the working Examples.

In all of the schemes described below, protecting groups for sensitiveor reactive groups are employed where necessary in accordance withgeneral principles of synthetic chemistry. Protecting groups aremanipulated according to standard methods of organic synthesis (T. W.Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis,John Wiley & Sons, incorporated by reference with regard to protectinggroups). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection of processes as well as the reaction conditionsand order of their execution shall be consistent with the preparation ofcompounds of formula (I).

Those skilled in the art will recognize if a stereocenter exists incompounds of formula (I). Accordingly, the present invention includesall possible stereoisomers and includes not only racemic compounds butthe individual enantiomers as well. When a compound is desired as asingle enantiomer, such may be obtained by stereospecific synthesis orby resolution of the final product or any convenient intermediate.Resolution of the final product, an intermediate, or a starting materialmay be affected by any suitable method known in the art. See, forexample, Stereochemistry of Organic Compounds by E. L. Eliel, S. H.Wilen, and L. N. Mander (Wiley-Interscience, 1994), incorporated byreference with regard to stereochemistry.

Representative AR modulator compounds, agonists, partial agonists, andantagonists according to the current invention include:

-   -   N-(cyclopropylmethyl)-N-(4-nitro-1-naphthyl)-N-propylamine;    -   N-cyclohexyl-N-methyl-4-nitro-1-naphthalenamine;    -   N-(4-nitro-1-naphthyl)-N,N-dipropylamine;    -   N-butyl-N-methyl-N-(4-nitro-1-naphthyl)amine;    -   4-[ethyl(2-methyl-2-propenyl)amino]-1-naphthonitrile;    -   N-butyl-N-ethyl-4-nitro-1-naphthalenamine;    -   4-[butyl(methyl)amino]-1-naphthonitrile;    -   4-[(cyclopropylmethyl)(propyl)amino]-1-naphthonitrile;    -   N¹-ethyl-N²,N²-dimethyl-N¹-(4nitro-1-naphthyl)-1,2-ethanediamine;    -   4-(propylamino)-1-naphthonitrile;    -   4-[(3-hydroxypropyl)amino]-1-naphthonitrile;    -   3-[(4-nitro-1-naphthyl)amino]propan-1-ol;    -   4-[(cyclopropylmethyl)amino]-1-naphthalenecarbonitrile;    -   4-(cyclopropylmethyl)[3-(1-piperidinyl)propyl]amino-1-naphthalenecarbonitrile        trifluoroacetate;    -   4-[(cyclopropylmethyl)(3-hydroxypropyl)amino]-1-naphthalenecarbonitrile;    -   4nitro-N-(2,2,2-trifluoroethyl)-1-naphthalenamine;    -   4-bromo-N-(2,2,2-trifluoroethyl)-1-naphthalenamine;    -   4-bromo-N,N-bis(2,2,2-trifluoroethyl)-1-naphthalenamine;    -   4-[(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile;    -   4-[bis(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile;    -   4-[propyl(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile;    -   4-[2-propen-1-yl(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile;        and    -   4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile.

ABBREVIATIONS

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, thefollowing abbreviations may be used in the examples and throughout thespecification:

-   -   g (grams);    -   L (liters);    -   μL (microliters);    -   M (molar);    -   Hz (Hertz);    -   mol (moles);    -   RT (room temperature);    -   min (minutes);    -   mp (melting point);    -   t_(R) (retention time);    -   TEA (triethylamine);    -   TFAA (trifluoroacetic anhydride);    -   CDCl₃ (deuterated chloroform);    -   SiO₂ (silica);    -   EtOAc (ethyl acetate);    -   HCl (hydrochloric acid);    -   mg (milligrams);    -   mL (milliliters);    -   psi (pounds per square inch);    -   mM (millimolar);    -   MHz (megahertz);    -   mmol (millimoles);    -   h (hours);    -   TLC (thin layer chromatography);    -   RP (reverse phase);    -   TFA (trifluoroacetic acid);    -   THF (tetrahydrofuran);    -   CD₃OD (deuterated methanol);    -   DMSO (dimethylsulfoxide);    -   atm (atmosphere);    -   CHCl₃ (chloroform);    -   Ac (acetyl);    -   DMF (N,N-dimethylformamide);    -   Cs₂CO₃ (cesium carbonate);    -   Et (ethyl);    -   MeOH (methanol);    -   PS (polymer supported);    -   satd (saturated).    -   Me (methyl);    -   EtOH (ethanol);    -   tBu (tert-butyl);    -   PPTS (pyridinium p-toluenesulfonate);    -   NMM (N-methyl morpholine);

Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Centigrade). All reactions conducted under an inert atmosphereat room temperature unless otherwise noted.

¹H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, aVarian Unity400 instrument, or a General Electric QE-300. Chemicalshifts are expressed in parts per million (ppm, δ units). Couplingconstants are in units of hertz (Hz). Splitting patterns describeapparent multiplicities and are designated as s (singlet), d (doublet),t (triplet), q (quartet), m (multiplet), or br (broad).

Method A

Compounds of formula (I) can be prepared starting from electrondeficient arenes and utilizing solid supported reagents (Scheme 1). Therequisite arenes are treated with primary or secondary non-cyclic aminesin the presence of a solid supported base such as N-methyl morpholine toafford the corresponding aniline. Excess halo arene can be scavengedwith polymer supported trisamine, while excess amine can be scavengedwith polymer supported isocyanate.

Method B

Compounds of formula (I) can also be prepared without the use of solidsupported reagents (Scheme 2). The requisite electron deficient arenesare treated with primary or secondary non-cyclic amines in the presenceof a base such as cesium carbonate to afford the corresponding aniline.

Compounds of formula (I) can be generated or further elaborated byreductive alkylation with an aldehyde and a reducing agent in thepresence of an acid and/or by direct alkylation with an alkylating agentin the presence of base such as sodium hydride (Scheme 3).

EXAMPLES

Method A Representative Procedure

Example 1

N-(Cyclopropylmethyl)-N-(4-nitro-1-naphthyl)-N-propylamine

Solid supported N-methyl morpholine (PS-NMM) Resin (0.045 g, 180 μmol),a 2 M solution of (cyclopropylmethyl)propylamine in DMSO (120 μL, 0.24mmol), and a 1 M solution of 4-chloro-1-nitronaphthalene in DMSO (150μL, 0.12 mmol) were added to a well of a Robbins FlexChem square wellplate. The plate was rotated for 20 h at 99° C. and cooled. To the wellwas added 1.2 mL of DMSO, solid supported benzylisocyanate(PS-Isocyanate) (0.136 g, 150 μmol), and solid supported tris amine(PS-Trisamine) (0.061 g, 150 μmol). The plate was rotated at 99° C. for12 h. The solvent in the well was collected via filtration. The resinswere rinsed with 0.5 mL DMSO, and the organic solutions were combinedand concentrated in vacuo at 60° C. to afford an analytically pureyellow solid (0.032 g, 95%): ¹H NMR (CDCl₃, 400 MHz) δ 8.75 (d, J=7.6Hz, 1H), 8.31 (d, J=8.5 Hz, 2H), 7.68 (dd, J=8.1, 8.1 Hz, 1H), 7.55 (dd,J=7.9, 7.9 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 3.42 (t, J=7.1 Hz, 2H), 3.20(d, J=6.8 Hz, 2H), 1.58 (sex, J=7.3 Hz, 2H ), 0.96 (sept, J=4.9 Hz, 1H),0.90 (t, J=7.5 Hz, 3H), 0.45 (q, J=5.3 Hz, 2H), 0.04 (q, J=4.9 Hz, 2H).TABLE 1 All entries in the table below were made according to method A.

MassSpec. ES m/z Example R¹ R² Compound Name (M + 1) 2 NO₂

N-cyclohexyl-N-methyl-4-nitro-1- naphthalenamine 285 3 NO₂

N-(4-nitro-1-naphthyl)-N,N- dipropylamine 273 4 NO₂

N-butyl-N-methyl-N-(4-nitro-1- naphthyl)amine 259 5 CN

4-[ethyl(2-methyl-2- propenyl)amino]-1-naphthonitrile 251 6 NO₂

N-butyl-N-ethyl-4-nitro-1- naphthalenamine 273 7 CN

4-[butyl (methyl)amino]-1- naphthonitrile 240Method B Representative Procedure

Example 1

N-(Cyclopropylmethyl)-N-(4-nitro-1-naphthyl)-N-propylamine

A DMSO (0.5 mL) solution of 1-chloro-4-nitronaphthalene (0.054 g, 0.26mmol, 1 equiv) was treated with cesium carbonate (0.120 g, 0.37 mmol,1.4 equiv) and (cyclopropylmethyl)propylamine (0.035 g, 0.31 mmol, 1.2equiv). After 3 h at 90° C., the cooled reaction was treated with H₂O (1mL), and extracted with EtOAc (3×1 mL). Concentration was followed byradial chromatography (SiO₂, 1 mm plate, 90:10; Hex/EtOAc) to afford thetitle compound as a yellow solid (0.063 g, 95%) with analytical datathat matched that for example 1 synthesized by method A.

Example 8

4-[(Cyclopropylmethyl)(propyl)amino]-1-naphthonitrile

Made in a manner similar to example 1, method B using4-fluoro-1-naphthonitrile as the electron deficient arene component: ¹HNMR (CDCl₃, 400 MHz) δ 8.30 (d, J=6.8 Hz, 1H), 8.19 (d, J=8.2 Hz, 1H),7.81 (d, J=8.1 Hz, 1H), 7.64 (dd, J=7.3, 7.3 Hz, 1H), 7.56 (dd, J=7.7,7.7 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 3.37 (t, J=7.1 Hz, 2H), 3.15 (d,J=6.4 Hz, 2H), 1.57 (sex, J=7.2 Hz, 2H), 0.96 (sept, J=5.2 Hz, 1H), 0.89(t, J=7.3 Hz, 3H), 0.44-0.42 (m, 2H), 0.01-0.00 (m, 2H).

Example 9

N¹-Ethyl-N²,N²-dimethyl-N¹-(4-nitro-1-naphthyl)-1,2-ethanediamine

Made in a manner similar to example 1, method B usingN¹-ethyl-N²,N²-dimethyl-1,2-ethanediamine as the amine component: ¹H NMR(CDCl₃, 400 MHz) δ 8.65 (d, J=8.8 Hz, 1H), 8.31 (d, J=8.4 Hz, 1H), 8.25(d, J=7.9 Hz, 1H), 7.72 (dd, J=7.0, 7.0 Hz, 1H), 7.64 (dd, J=7.3, 7.3Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 3.76 (t, J=6.4 Hz, 2H), 3.37 (q, J=7.1Hz, 2H), 3.20 (t, J=3.2 Hz, 2H), 2.82 (s, 6H), 1.07 (t, J=7.1 Hz, 3H).

Example 10

4-(Propylamino)-1-naphthonitrile

Synthesized in a manner similar to example 1, method B using4-fluoro-1-naphthonitrile and propylamine: MS (ES) m/z 211 (M+1).

Example 11

4-[(3-Hydroxypropyl)amino]-1-naphthonitrile

Prepared according to example 1, method B using4-fluoro-1-naphthonitrile and 3-aminopropan-1-ol: MS (ES) m/z 225 (M−1).

Example 12

3-[(4-Nitro-1-naphthyl)amino]propan-1-ol

Prepared according to example 1, method B using1-chloro-4-nitronaphthalene and 3-aminopropan-1-ol: MS (ES): m/z 245(M−1).

Example 13

4-[(Cyclopropylmethyl)amino]-1-naphthalenecarbonitrile

Prepared according to example 1, method B using4-fluoro-1-naphthonitrile and (cyclopropylmethyl)amine: MS (APCI) m/z223 (M+1).

Example 14

4-{(Cyclopropylmethyl)[3-(1-piperidinyl)propyl]amino}-1-naphthalenecarbonitriletrifluoroacetate

To a slurry of NaH (0.024 g of a 60% w/w suspension in mineral oil, 0.60mmol) and NaI (0.030 g, 0.20 mmol) in dry DMF (1 mL) at room temperaturewas added example 13 (0.044 g, 0.20 mmol) in one portion. The mixturewas stirred for 15 min and a solution of 1-(3-chloropropyl)piperidine(0.065 g, 0.40 mmol) in DMF (0.5 mL) was added. The mixture was heatedat 60° C. for 12 h, cooled and poured into 10% v/v HCl. The whole wasextracted with Et₂O (×2), treated with satd. Na₂CO₃ and extracted withEt₂O (×3). Ether extracts from the basic aqueous layer were combined andconcentrated in vacuo. The residue was purified by preparative HPLC (C18column, MeCN/water with 0.1% v/v TFA), affording 0.033 g of the titlecompound as an orange gum: MS (APCI) m/z 348 (M+1).

Example 15

4-[(Cyclopropylmethyl)(3-hydroxypropyl)amino]-1-naphthalenecarbonitrile

To a slurry of NaH (0.018 g of a 60% w/w suspension in mineral oil, 0.45mmol) in dry DMF (1 mL) at room temperature was added example 13 (0.067g, 0.30 mmol) in one portion. The mixture was stirred 20 min and[(3-bromopropyl)oxy](1,1-dimethylethyl)dimethylsilane (0.080 mL, 0.36mmol) was added via syringe. The mixture was stirred 20 h, poured intowater and the whole was extracted with Et₂O (×3). The combined organicportions were washed (water, brine) and concentrated in vacuo. Theresidue was dissolved in EtOH (2 mL) and PPTS (0.030 g) was added. Themixture was heated at 80° C. in a sealed vial for 2 h, cooled, andconcentrated in vacuo. The residue was purified by preparative HPLC (C18column, MeCN/water with 0.1% v/v TFA), affording 0.037 g of the titlecompound as a colorless gum: MS (APCI) m/z 281 (M+1).

Example 16

4-Nitro-N-(2,2,2-trifluoroethyl)-1-naphthalenamine

To a solution of 4-nitro-1-naphthalenamine (3.76 g, 20.0 mmol) in TFA(20 mL) at 0° C. was added NaBH₃CN (2.51 g, 40 mmol), portionwise over10 min (CAUTION: exothermic reaction with hydrogen evolution). Themixture was stirred 5 min and trifluoroacetaldehyde hydrate (5.76 g, 40mmol) was added, dropwise over 3 min. The flask was sealed with a rubberseptum, and placed under balloon pressure of nitrogen. The cooling bathwas removed and the mixture was stirred at room temp. for 12 h. Themixture was neutralized by slowly pouring into saturated NaHCO₃ (0° C.),and the whole was extracted with EtOAc (×3). The combined organicportions were washed (water, brine), dried over Na₂SO₄, filtered, andconcentrated to dryness. Recrystallization from EtOAc/hexanes afforded2.82 g of the title compound as bright yellow needles: MS (APCI) m/z 269(M−1).

Example 17

4-Bromo-N-(2,2,2-trifluoroethyl)-1-naphthalenamine

Synthesized as described in example 16 from 4-bromo-1-naphthalenamine:¹H NMR (300 MHz, DMSO-d₈) δ 8.25 (d, J=8.7 Hz 1H), 7.42 (overlapping dd,1H), 7.30-7.15 (m, 3H), 6.89 (d, J=7.9 Hz, 1H), 6.80 (t, J=6.6 Hz, 1H),4.17 (overlapping qd, 2H).

Example 18

4-Bromo-N,N-bis(2,2,2-trifluoroethyl)-1-naphthalenamine

To a solution of example 17 (0.253 g, 0.832 mmol) in TFA (3 mL) at 0° C.was added NaBH₃CN (0.261 g, 4.16 mmol), portionwise over 3 min. Themixture was stirred 5 min and trifluoroacetaldehyde hydrate (0.214 g,1.66 mmol) was added. The flask was sealed with a rubber septum, placedunder balloon pressure of nitrogen and the cooling bath was removed.Excess trifluoroacetaldehyde hydrate (2.14 g, 16.6 mmol) was added tothe stirred mixture via syringe pump over 15 h. The mixture was slowlypoured into saturated NaHCO₃ (0° C.) and the whole was extracted withEtOAc (×3). The combined organic portions were washed (water, brine),dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash chromatography (EtOAc/hexanes), affording 0.267 g ofthe title compound as a white solid: ¹H NMR (300 MHz, acetone-d₆) δ 8.34(d, J=8.5 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.60 (overlapping ddd, 1H),7.51 (d, J=7.6 Hz, 1H), 7.37 (overlapping ddd, 1H), 7.29 (d, J=8.3 Hz,1H), 4.30 (q, J=9.1 Hz, 4H).

Example 19

4-[(2,2,2-Trifluoroethyl)amino]-1-naphthalenecarbonitrile

Synthesized as described in example 16 from4-amino-1-naphthalenecarbonitrile: ¹H NMR (300 MHz, CDCl₃) δ 8.22 (d,J=8.3 Hz, 1H), 7.87-7.78 (m, 2H), 7.70 (overlapping ddd, 1H), 7.61(overlapping ddd, 1H), 6.71 (d, J=8.3 Hz, 1H), 5.19 (br. t, J=6.4 Hz,1H), 4.05 (overlapping qd, 2H).

Example 20

4-[Bis(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile

Synthesized as described in example 18 using example 19: MS (EI) m/z 332(M⁺, 86%), 263 ([M−CF₃]⁺, 100%).

Example 21

4-[Propyl(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile

To a slurry of hexanes-washed NaH (0.033 g of a 60% w/w suspension inmineral oil; 0.82 mmol) in dry DMF (2 mL) at 0° C. was added a solutionexample 19 (0.102 g, 0.41 mmol) in DMF (1 mL), dropwise over 2 min. Themixture was stirred 20 min, 1-iodopropane (0.080 mL, 0.82 mmol) wasadded and the cooling bath was removed.

After stirring 12 h at rt, the mixture was poured into water and thewhole extracted with ether (×3). The combined organic portions werewashed (water, brine), dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash chromatography (EtOAc/hexanes),affording 0.076 g of the title compound as a colorless gum: ¹H NMR (400MHz, MeOHd₄) δ 8.31 (d, J=8.3 Hz, 1H), 8.15 (d, J=8.3 Hz, 1H), 7.94 (d,J=7.9 Hz, 1H), 7.72 (overlapping ddd, 1 H), 7.66 (overlapping ddd, 1H),7.46 (d, J=8.0 Hz, 1H), 4.04 (q, J=9.3 Hz, 2H), 3.38 (t, J=7.4 Hz, 2H),1.53 (overlapping qt, 2H), 0.85 (t, J=7.4 Hz, 3H).

Example 22

4-[2-Propen-1-yl(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile

Synthesized as described in example 21 from example 19 and allylbromide: ¹H NMR (400 MHz, MeOH-d₄) δ 8.33 (d, J=8.4 Hz, 1H), 8.16 (d,J=8.4 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.74 (overlapping ddd, 1H), 7.68(overlapping ddd, 1H), 7.45 (d, J=8.0 Hz, 1H), 5.88 (ddt, J=17.0, 10.3,6.5 Hz, 1H), 5.28-5.17 (m, 2H), 4.04 (q, J=9.2 Hz, 2H), 3.96 (d, J=6.5Hz, 2H).

Example 23

4-[(2-Hydroxyethyl)(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile

A mixture of example 19 (1.00 g, 4.00 mmol), methyl bromoacetate (1.89mL, 20.0 mmol) and anhydrous K₂CO₃ (2.76 g, 20.0 mmol) in dry MeCN (10mL) was refluxed under nitrogen for 22 h. The mixture was cooled, Cs₂CO₃(6.5 g, 20 mmol) and additional methyl bromoacetate (1.89 mL, 20 mmol)were added, and reflux was resumed. After 14 h, the mixture was cooled,poured into water and the whole extracted with EtOAc (×3). The combinedorganic portions were washed with brine, dried over Na₂SO₄, filtered andconcentrated to dryness, affording 0.883 g of a colorless solid that wasused without further purification. The crude solid was dissolved in dryTHF (10 mL), cooled to 0° C., and a solution of LiBH₄ in THF (2.74 mL ofa 2.0 M solution, 5.49 mmol) was added dropwise over 3 min. The coolingbath was removed and the mixture stirred 72 h at room temp. The mixturewas cooled to 0° C., quenched by dropwise addition of saturated NH₄Cl,poured into water and the whole extracted with EtOAc (×3). The combinedorganic portions were washed (water, brine), dried over Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by flashchromatography (EtOAc/hexanes), affording 0.638 g of the title compoundas a colorless syrup which slowly solidified: MS (APCI) m/z 295 (M+1).

Compounds of the current invention are modulators of the androgenreceptor, glucocorticoid receptor, the mineralocorticoid receptor,and/or the progesterone receptor. Activity mediated through theseoxosteroid nuclear receptors was determined using the following in vitroand in vivo assays.

In Vitro Assays:

The following abbreviations and sources of materials are used

-   Fluormone PL Red—a commercially available PR fluoroprobe (PanVera    Corp, Product No P2965)-   Fluormone GS Red—a commercially available GR fluoroprobe (PanVera    Corp, Product No P2894)-   Fluormone AL Green—a commercially available AR fluoroprobe (PanVera    Corp, Product No P3010)-   PR-LBD—Purified human progesterone ligand binding domain tagged with    Glutathione Transferase (PanVera Corp, Product No P2900)-   GR—purified human glucocorticoid receptor (PanVera Corp, Product No    P2812)-   AR-LBD—Purified rat androgen ligand binding domain tagged with    Glutathione Transferase (PanVera Corp, Product No P3009)-   PR Screening Buffer—100 mM potassium phosphate (pH 7.4), 100 μG/mL    bovine gamma globulin, 15% ethylene glycol, 0.02% NaN₃, 10% glycerol    (PanVera Corp Product No P2967) with 0.1% wlv CHAPS-   AR Screening Buffer—pH 7.5 containing protein stabilizing agents and    glycerol (PanVera Corp Product No P3011)-   GR Screening Buffer—100 mM potassium phosphate (pH 7.4), 200 mM    Na₂MoO₂, 1 mM EDTA, 20% DMSO (PanVera Corp Product No P2814) with GR    stabilizing peptide (100 μM) (PanVera Corp Product No P2815)-   DTT—dithiothreitol (PanVera Corp Product No P2325)-   Discovery Analyst—is an FP reader-   DMSO—dimethylsulphoxide    Progesterone Receptor Fluorescence Polarization Assay:

The progesterone receptor fluorescence polarization assay is used toinvestigate the interaction of the compounds with the progesteronereceptor.

Compounds are added to the 384 well black plates to a final volume of0.5 μL. Sufficient Fluormone PL Red and PR-LBD are defrosted on ice togive a final concentration of 2 nM and 40 nM, respectively. PR screeningbuffer is chilled to 4° C. prior to addition of DTT to give a finalconcentration of 1 mM. The Fluormone PL Red and PR-LBD in PR ScreeningBuffer are added to compound plates to give a final volume of 10 μL. Theassay is allowed to incubate at 20-22° C. for 2 hours. The plates arecounted in a Discovery Analyst with suitable 535 nM excitation and 590nM emission interference filters. Compounds that interact with the PRreceptor result in a lower fluorescence polarization reading. Testcompounds are dissolved and diluted in DMSO. Compounds are assayed insinglicate, a four parameter curve fit of the following form beingapplied $y = {\frac{a - d}{1 + ( \frac{x}{c} )^{b}} + d}$where a is the minimum, b is the Hill slope, c is the IC₅₀ and d is themaximum. Maximum and minimum values are compared to adhesion in theabsence of compound and in the presence of 10⁻⁵M progesterone. Data ispresented as the mean pIC₅₀ with the standard error of the mean of nexperiments. Compounds with pIC₅₀ greater than 5.0 and a % max greaterthan 50 are considered desirable.Androgen Receptor Fluorescence Polarization Assay:

The androgen receptor fluorescence polarization assay is used toinvestigate the interaction of the compounds with the androgen receptor.

Compounds are added to the 384 well black plates to a final volume of0.5 μL. Sufficient Fluormone AL Green and AR-LBD are defrosted on ice togive a final concentration of 1 nM and 25 nM, respectively. AR screeningbuffer is chilled to 4° C. prior to addition of DTT to give a finalconcentration of 1 mM. The Fluormone AL Green and AR-LBD in AR ScreeningBuffer are added to compound plates to give a final volume of 10 μL. Theassay is allowed to incubate at 20° C. for 5 hours. The plates arecounted in a Discovery Analyst with suitable 485 nM excitation and 535nM emission interference filters. Compounds that interact with the ARreceptor result in a lower fluorescence polarization reading. Testcompounds are dissolved and diluted in DMSO. Compounds are assayed insinglicate, a four parameter curve fit of the following form beingapplied $y = {\frac{a - d}{1 + ( \frac{x}{c} )^{b}} + d}$where a is the minimum, b is the Hill slope, c is the IC₅₀ and d is themaximum. Maximum and minimum values are compared to adhesion in theabsence of compound and in the presence of 10⁻⁵M dihydrotestosterone.Data is presented as the mean pIC50 with the standard error of the meanof n experiments. Compounds with pIC₅₀ greater than 5.0 and a % maxgreater than 50 are considered desirable.Glucocorticold Receptor Fluorescence Polarization Assay

The glucocorticoid receptor fluorescence polarization assay is used toinvestigate the interaction of the compounds with the glucocorticoidreceptor.

Compounds are added to the 384 well black plates to a final volume of0.5 μL. Sufficient Fluormone GS Red and GR are defrosted on ice to givea final concentration of 1 nM and 4 nM, respectively. GR screeningbuffer is chilled to 4 ° C. prior to addition of DTT to give a finalconcentration of 1 mM. The Fluormone GS Red, and GR in GR ScreeningBuffer are added to compound plates to give a final volume of 10 μL. Theassay is allowed to incubate at 4° C. for 12 hours. The plates arecounted in a Discovery Analyst with suitable 535 nM excitation and 590nM emission interference filters. Compounds that interact with the GRreceptor result in a lower fluorescence polarization reading. Testcompounds are dissolved and diluted in DMSO. Compounds are assayed insinglicate, a four parameter curve fit of the following form beingapplied $y = {\frac{a - d}{1 + ( \frac{x}{c} )^{b}} + d}$where a is the minimum, b is the Hill slope, c is the EC₅₀ and d is themaximum. Maximum and minimum values are compared to adhesion in theabsence of compound and in the presence of 10⁻⁵ M dexamethasone. Data ispresented as the mean pIC₅₀ with the standard error of the mean of nexperiments. Compounds with pIC₅₀ greater than 5.0 and a % max greaterthan 50 are considered desirable.Transient Transfection Assay:

Cotransfection assays using full-length hAR were performed in CV-1 cells(monkey kidney fibroblasts). The cells were seeded in charcoal-strippedmedium in 96-well plates (24,000 cells/well) and incubated overnight.Transient transfections were carried out using the following plasmids:pSG5-AR, MMTV LUC reporter, β-actin SPAP, and pBluescript (filler DNA).The cell plates were then incubated for 6-20 hours. The transfectionmixture was washed away and then the cells were drugged with dosesranging from 10⁻¹⁰ to 10⁻⁵. Two replicates were used for each sample.Incubation with drug was continued for 14 hours. A spectrophotometer wasused for SPAP measurements, while a topcounter was used to read theresults from the luciferase assay. The ratio of luciferase activity toSPAP activity was calculated to normalize the variance in cell numberand transfection efficiency.

Data Analysis:

Data were reduced using RoboFit99. The results were expressed as percentof maximum as calculated by the following formulas:${{fold}\quad{activation}} = \frac{( {( \frac{({Luc})}{( {{SPAP} - {{SPAP}\quad{substrate}\quad{blank}\quad{{avg}.}}} )} ) - {{basal}\quad{activation}}} )}{{basal}\quad{activation}^{*}}$*basal activation per plate=(Luc vehicle)/(SPAP vehicle−substrate blankaverage)% max.=(^(fold activation of unknown)/posive control fold activationavg.)×100

Curves were fit from these data using RoboFit to determine EC₅₀'s foragonists and IC₅₀'s for antagonists using the following equation:Y=((Vmax*x)/(K+x))+Y2

These values were converted to pEC₅₀'s and pIC₅₀'s for posting by usingthe following equations:pEC ₅₀=−log(EC ₅₀)pIC ₅₀=−log(IC ₅₀)

For antagonist assays, the percent maximum response antagonist wascalculated by the following formula in which Y_(min) and Y_(max) arecurve asymptotes at the maximum or minimum concentration tested:% max. resp. ant.=100*(1−Y _(min) /Y _(max))

For antagonist assays, pKb's were calculated using the followingformula:pKb=IC ₅₀ of unknown/((1+*conc.*)/DHT EC ₅₀ average)where *conc.*=concentration of DHT used as the agonist in the medium forthe antagonist experiment, expressed in nM. This concentration was setat twice pEC₅₀. This would be 0.2 for AR.

Compounds with a pXC₅₀ greater than 5.0 are considered desirable.

Castrated Male Rat Model (ORX Rat)

The activity of the compounds of the present invention as modulators ofthe androgen receptor was investigated using a castrated male rat model(ORX) as described in C. D. Kockakian, Pharmac. Therap. B 1(2), 149-177(1975); C. Tobin and Y. Joubert, Developmental Biology 146, 131-138(1991); J. Antonio, J. D. Wilson and F. W. George, J Appl. Physiol.87(6) 2016-2019 (1999)) the disclosures of which herein are included byreference.

It has been well defined that androgens play important roles in themaintenance and growth of many tissues in both animals and humans.Muscles, like the levator ani and bulbocavernosus, and sexual accessoryorgans, such as the prostate glands and seminal vesicles have highexpression levels of the androgen receptor and are known to respondquickly to exogenous androgen addition or androgen deprivation throughtesticular ablation. Castration produces dramatic atrophy of muscle andsexual accessory organs; whereas the administration of exogenousandrogens to the castrated animal results in effective hypertrophy ofthese muscles and sexual accessory organs. Although the levator animuscle, also known as the dorsal bulbocavernosus, is not ‘true skeletalmuscle’ and definitely sex-linked, it is reasonable to use this muscleto screen muscle anabolic activities of test compounds because of itsandrogen responsiveness and simplicity of removal.

Male Sprague-Dawley rats weighing 160-180 grams were used in the assay.The rats were singly caged upon receiving and throughout the study.Bilateral orchidectomies were performed in sterilized surgicalconditions under isoflurane anesthesia. An anteroposterior incision wasmade in the scrotum. The testicles were exteriorized and the spermaticartery and vas deferens were ligated with 4.0 silk 0.5 cm proximal tothe ligation site. The testicles then were removed by a surgicalscissors distal to the ligation sites. The tissue stumps were returnedto the scrotum, the scrotum and overlying skin were closed by a surgicalstapler. The Sham-ORX rats underwent all procedures except ligation andscissors cutting. The rats were assigned randomly into study groups 7-10days post surgery based on the body weight.

Dihydrotestosterone (DHT) was used as a positive control (1-10 mg/kgs.c.). Compounds of the current invention were administeredsubcutaneously or orally for 4-28 days. The rats were weighed daily anddoses were adjusted accordingly. The general well being of the animalwas monitored throughout the course of the study.

At the end of the study, the rats were euthanized in a CO₂ chamber. Theventral prostate glands(VP), seminal vesicles(SV), levator animuscle(LA) and lo bulbocavernosus(BC) were carefully dissected. Thetissues were blotted dry, the weights were recorded, and then saved forhistological and molecular analysis. The VP and SV weights serve asandrogenic indicators and LA and BC are anabolic indicators. The ratioof anabolic to androgenic activities was used to evaluate the testcompounds. Serum luteinizing hormone(LH), follicle stimulatinghormone(FSH) and other potential serum markers of anabolic activitieswere also analyzed.

In general, desirable compounds show levator ani hypertrophy and verylittle prostate stimulation

Test compounds were employed in free or salt form.

All research complied with the principles of laboratory animal care (NIHpublication No. 85-23, revised 1985) and GlaxoSmithKline policy onanimal use.

Although specific embodiments of the present invention are hereinillustrated and described in detail, the invention is not limitedthereto. The above detailed descriptions are provided as exemplary ofthe present invention and should not be construed as constituting anylimitation of the invention. Modifications will be obvious to thoseskilled in the art, and all modifications that do not depart from thespirit of the invention are intended to be included within the scope ofthe appended claims.

1-7. (canceled)
 8. A compound of Formula (I)

or a salt or solvate thereof, wherein R¹ is cyano, nitro, halogen,haloalkyl, heterocyclyl, hydroxy, alkoxy, haloalkoxy, —OC(O)⁶, —CO₂R⁶,—CONHR⁶, —C(O)R⁶, —S(O)_(n)R⁶, —SO₂N(R⁶)₂, —NHC(O)R⁶, or —NHSO₂R⁶; R² isH, cyano, nitro, halogen, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy,alkoxy, haloalkoxy, —OC(O)R⁶, or aryl; R³ and R⁴ each are independently—(CH₂)_(x)—R⁵, where x is 0 to 6, and R⁵ is selected from H, alkyl,hydroxy, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,—C(O)OR⁷, or —N(R⁸)₂; each R⁶ independently is H, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, orheteroaralkyl; each R⁷ independently is H, alkyl, cycloalkyl, aryl; eachR⁸ independently is H or alkyl; and R⁹ is H, cyano, nitro, halogen,haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, haloalkoxy,—OC(O)R⁸, or aryl; and the compound is selected from:N-(cyclopropylmethyl)-N-(4-nitro-1-naphthyl)-N-propylamine;N-cyclohexyl-N-methyl-4-nitro-1-naphthalenamine;N-(4-nitro-1-naphthyl)-N,N-dipropylamine;N-butyl-N-methyl-N-(4-nitro-1-naphthyl)amine;4-[ethyl(2-methyl-2-propenyl)amino]-1-naphthonitrile;N-butyl-N-ethyl-4-nitro-1-naphthalenamine;4-[butyl(methyl)amino]-1-naphthonitrile;4-[(cyclopropylmethyl)(propyl)amino]-1-naphthonitrile;N¹-ethyl-N²,N²-dimethyl-N′-(4-nitro-1-naphthyl)-1,2-ethanediamine;4-(propylamino)-1-naphthonitrile;4-[(3-hydroxypropyl)amino]-1-naphthonitrile;3-[(4-nitro-1-naphthyl)amino]propan-1-ol;4-[(cyclopropylmethyl)amino]-1-naphthalenecarbonitrile;4-{(cyclopropylmethyl)[3-(1-piperidinyl)propyl]amino}-1-naphthalenecarbonitrile trifluoroacetate;4-[(cyclopropylmethyl)(3-hydroxypropyl)amino]-1-naphthalenecarbonitrile;4-nitro-N-(2,2,2-trifluoroethyl)-1-naphthalenamine;4-bromo-N-(2,2,2-trifluoroethyl)-1-naphthalenamine;4-bromo-N,N-bis(2,2,2-trifluoroethyl)-1-naphthalenamine;4-[(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile;4-[bis(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile;4-[propyl(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile;4-[2-propen-1-yl(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile;and4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-1-naphthalenecarbonitrile.9. (canceled)
 10. A pharmaceutical composition comprising a compoundaccording to claim 8, and a pharmaceutically acceptable carrier. 11-15.(canceled)
 16. A method for the treatment or prophylaxis of conditionsor disorders that respond to selective androgen receptor modulationcomprising the administration of a compound according to claim
 8. 17. Amethod for the treatment or prophylaxis of osteoporosis, muscle wasting,frailty, cardiovascular disease, breast cancer, uterine cancer,prostatic hyperplasia, prostate cancer, dyslipidemia, menopausalvasomotor conditions, urinary incontinence, artherosclerosis, libidoenhancement, depression, uterine fibroid disease, aortic smooth musclecell proliferation, endometriosis, or ADAM comprising the administrationof a compound according to claim 8.